Fluid resuscitation is a very important initial step in the management of hypovolemic critically ill patients. After the publication of starch trials, crystalloids have become the first-line resuscitation fluid for all critical patients unless blood is required for ongoing massive blood loss. Guidelines recommend initial crystalloid bolus of 20–30 mL/Kg to treat the hypovolemia in sepsis and septic shock patients.1 Four phases have been identified in the management of circulatory shock—salvage, optimization, stabilization and de-escalation (SOSD).2
SOSD PHASES OF RESUSCITATION
Initial salvage phase focuses on restoration of vital organ perfusion by bringing hemodynamic parameters to acceptable levels and large volume crystalloid resuscitation is required in initial 0–24 hours, followed by optimization and stabilization phase lasting 24–72 hours where smaller volume are required to maintain fluid status and the focus is prevention of organ dysfunction after hemodynamic stability has been achieved and the last de-escalation or de-resuscitation phase after 96 hours, aims to achieve slight negative balance by either fluid restriction or induced diuresis.3
Intravenous fluids administration is important not only in the management of critically ill patients, but also in the patients undergoing major surgical procedures. Large volume crystalloid resuscitation has been identified as the cause of deterioration in some situations like acute respiratory distress syndrome (ARDS) and can lead to tissue edema due to increased interstitial volume, secondary abdominal compartment syndrome, decreased cardiac function, increased gastric mucosal permeability leading to bacterial translocation.
WHAT ARE CRYSTALLOIDS?
Crystalloids are sodium-based solutions which contain electrolytes in concentration similar to the plasma. Different crystalloids vary in several ways including chloride content, strong ion difference (SID) and osmolality. Traditionally crystalloids have been labeled as isotonic because the osmolality is similar to intravascular fluid and they can be infused fast in situations of ongoing intravascular fluid loss with few contraindications. They are cheap, do not require special storage, have extended shelf life and can be rapidly administered. Unlike colloids, they readily cross out of intravascular space to replenish fluid in the interstitial compartment. The interstitial fluid moves into the intracellular and intravascular spaces in shock, depleting the interstitial space. Crystalloids can affect the balance of body fluids in only these two compartments. The commonly used crystalloids are listed in Table 1.
TYPES OF CRYSTALLOIDS
The most commonly used crystalloid solution is normal saline (saline, 0.9% NaCl or NS or isotonic saline solution, ISS). Saline contains 9 g of sodium chloride in 1 L of water (0.9%) and contains 154 mEq/L of sodium and 154 mEq/L of chloride. The chloride content is about 1.5 times higher than plasma, osmotic pressure is 286 mOsm/L (similar to intravascular and interstitial fluid) and has a strong ion deficit of zero.4 Aggressive fluid resuscitation with saline may cause dilution of circulating bicarbonate resulting in hyperchloremic acidosis proportional to volume infused. Saline is mainly distributed in the interstitium (75%) and to a lesser extent in the intravascular compartment (25%). Therefore, the volume required to raise intravascular compartment is high.
Crystalloids such as Ringer's lactate (RL; Hartmann's) solution, Plasma-Lyte, Normosol and similar solutions are currently labeled as “physiologically balanced” crystalloids, as their electrolyte contents are similar to the human plasma. These balanced crystalloids are nearly isotonic with a chloride concentration <110 mEq/L and the SID close to plasma. RL solution is widely used in clinical practice and contains 130 mmol of Na+, 4 mmol of K+, 3 mmol Ca++ and 109 mmol of Cl─ per liter. RL is metabolized in liver by gluconeogenesis and oxidation, where one H+ ion is removed, leaving an OH─ to combine with CO2 to form HCO3. In a normal liver, infusion of 1 L of RL can produce 29 mmol of HCO3. Its clinical use is limited by distribution of only 25% in the intravascular space like normal saline, necessitating large infusions and a lower osmolality, which can result in cerebral edema in head injury patients.
In diabetic patients on metformin, the ability of liver to metabolize lactate is altered resulting in metabolic alkalosis. Since liver metabolizes more than half of circulating RL, the body's capacity to metabolize lactate is not well-preserved in liver disease. Infusion of RL is associated with a 30% increase in oxygen consumption, which may adversely impact critical patients with pre-existing tissue hypoxia. Use of large volume of RL may also affect the value of lactate as a predictor of mortality.
Newer crystalloids like Plasma-Lyte have been labeled as “balanced” or “physiologic” solutions and are derivatives of the original Hartmann's and Ringer's solutions. But, none of these solutions are either truly balanced or physiologic. These solutions are relatively hypotonic because they have a lower Na+ concentration than extracellular fluid. As bicarbonate-containing solutions are unstable in plastic containers, these solutions use alternative anions, such as lactate, acetate, gluconate and malate for buffering.
Excessive administration of balanced salt solutions may result in hyperlactatemia, metabolic alkalosis and hypotonicity (with compound sodium lactate) and cardiotoxicity (with acetate). The addition of calcium ions may generate microthrombi with citrate containing red-cell transfusions. Acetate in balanced salt solutions does not require hepatic metabolism and is readily metabolized to CO2 and water and the increase in oxygen consumption is less than lactate. Acetate or gluconate combined buffer may offer a higher buffering capacity.
NORMAL SALINE VERSUS BALANCED CRYSTALLOIDS
Resuscitation with 0.9% saline in animal models of hemorrhagic shock was found to be associated with hyperchloremic metabolic acidosis when compared to a balanced solution (RL or Plasma-Lyte). Renal blood flow and kidney oxygen consumption was improved with Plasma-Lyte resuscitation. In a rat model of abdominal sepsis, resuscitation with Plasma-Lyte was associated with maintenance of plasma chloride levels and arterial pH. It was associated with a lower plasma creatinine, lower urinary cystatin C, lower neutrophil gelatinase-associated lipocalin (NGAL), lower plasma interleukin-6 (IL-6), lower incidence and severity of acute kidney injury and a higher survival when compared with 0.9% saline. There was no difference in serum potassium levels between the two groups.6 Normal saline is associated with renal dysfunction7 due to renal vasoconstriction and cortical hypoperfusion, impairment of immune function8 with potentially decreased in-hospital survival.9
Studies in healthy volunteers comparing the effects of 0.9% saline, Plasma-Lyte, RL or Hartmann's solution have reported hyperchloremic metabolic acidosis following a 0.9% saline infusion and a lower urinary output. The infusion of 50 mL/kg of RL was associated with a transient decrease in serum osmolality and increase in venous pH in these volunteers.5
In a double-blind crossover study on healthy volunteers,10 the effects of a bolus of 2 L infusions of 0.9% saline (NaCl) and Hartmann's solution were compared in healthy subjects. Blood and plasma volume expansion were greater and more sustained after saline than after Hartmann's solution (p <0.01). More than 56% of the infused saline was retained, in contrast with only 30% of the Hartmann's solution after 6 hours. The urine output with higher sodium content was more after Hartmann's than after saline. There were no significant differences between the effects of the two solutions on serum sodium, potassium, urea or osmolality. After saline, all subjects developed hyperchloremia (>105 mmol/L), which was sustained for >6 hours, while serum chloride concentrations remained normal after Hartmann's. Serum bicarbonate concentration was significantly lower after saline than after Hartmann's.
The same group compared 0.9% saline with Plasma-Lyte (2 L within 1 h) in healthy volunteers on two separate occasions.11 The intravascular volume expansion was similar between Plasma-Lyte and 0.9% saline. But use of 0.9% saline was associated with sustained hyperchloremia, reduced SID, increased extravascular volume (edema) and lowered diuresis compared with Plasma-Lyte. Although there was difference in urinary NGAL, but renal artery flow velocity and renal cortical perfusion assessed with magnetic resonance imaging were significantly lower after 0.9% saline administration than after Plasma-Lyte.
A data based observational study evaluating adult patients undergoing major open abdominal surgery who received either 0.9% saline (30,994 patients) or a balanced crystalloid solution (926 patients) on the day of surgery found higher in-hospital mortality in the saline group compared to balanced group (5.6% vs. 2.9%, p <0.001). The incidence of postoperative infection, renal failure requiring dialysis, blood transfusion and electrolyte disturbance and acidosis, investigation were more frequent in patients receiving 0.9% saline.9
A single center prospective, open label, sequential period pilot study of 760 patients assessing the association of a chloride-restrictive (vs. chloride-liberal) intravenous fluid strategy with acute kidney injury in critically ill patients, found that the implementation of a chloride-restrictive strategy in a tertiary intensive care unit (ICU) was associated with a significant decrease in the incidence of acute kidney injury and use of renal replacement therapy (RRT), although there were no differences in hospital mortality, hospital or ICU length of stay, or need for RRT after hospital discharge.12
The SPLIT (0.9% saline vs. Plasma-Lyte 148 for intensive care fluid therapy) trial13 from New Zealand compared the effect of buffering crystalloids (Plasma-Lyte) with saline on renal complications in ICU patients. It was a multicenter double-blind, cluster randomized double crossover trial done in medical and surgical ICUs. The study did not find a higher risk of acute kidney injury with saline when compared to buffered crystalloid. The study was criticized for a small exposure of fluid (1–2 L), less critical patients [Mean Acute Physiology and Chronic Health Evaluation (APACHE) II of 14] and a predominantly postoperative population.
Recently published pragmatic trials from SMART14 (Isotonic Solutions and Major Adverse Renal Events Trial) and SALT-ED15 (Saline against Lactated Ringer's or Plasma-Lyte in the Emergency Department) investigators group in US are from a single academic center and involve multiple critical care units. The study was coordinated between ED, ICUs, operating room (OR) to maintain uniformity in the type of fluid used. When the patients were critically ill and admitted to ICU from the ED, they were enrolled in SMART trial (Jan 2015 to Jan 2017) and when they were noncritical and admitted outside the ICU, they were enrolled in SALT-ED trial (Jan 2016 to Jan 2017).
About 15,802 critical patients were cluster randomized to receive either saline (0.9% sodium chloride) or balanced crystalloids (Lactated Ringer's solution or Plama-Lyte A). Patients received the same fluid in respective ICUs as they received in ED or OR to maintain uniformity. However, need based crossover was allowed at the clinician's discretion. The relative contraindications to the use of balanced crystalloids like hyperkalemia, brain injury were predefined and such patients were treated with normal saline. The primary outcome was a major adverse kidney event within 30 days and was a composite of death, new RRT, or persistent renal dysfunction. The study showed a significantly lower incidence of a major kidney adverse event within 30 days (14.3%) in the balanced crystalloid group (n = 7,942) as compared to (15.4%) the saline group (n = 7,860).
The SALT-ED trial engaged 13,347 patients who were treated with 1,079 mL of intravenous crystalloids in the emergency department and were later admitted in the hospital outside an ICU. The type of crystalloid assigned to the patient was based on the calendar month and the emergency department crossed over between saline and balanced crystalloids on a monthly basis. The primary outcome was hospital-free days (days alive after discharge before day 28). Secondary outcomes included major adverse kidney events within 30 days derived from a composite as in SMART trial. Total 95% of the patients in balanced crystalloid group were treated with RL solution. The large study concluded that there was no difference in hospital-free days between treatment with balanced crystalloids or saline in noncritically ill adults treated with intravenous fluids in the emergency department. Patients in the balanced crystalloid group had lower incidence of major adverse kidney events within 30 days (5.6% vs. 4.7%, p = 0.01). Patients who had presented to the ED with renal dysfunction or hyperchloremia appeared to have the largest benefit from balanced crystalloids.
Although normal saline (0.9% NaCl) is one of the most commonly used intravenous fluid in resuscitation, there is increasing awareness that large volume resuscitation with saline can lead to potentially harmful normal anion gap hyperchloremic metabolic acidosis, a higher incidence of acute kidney injury or the need of RRT in the critically ill patients. Comparison of saline with balanced crystalloids has been a debatable subject in recent times, but newer large scale studies favor the use of balanced crystalloids over saline in critically ill patients.
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- Vincent JL, DeBacker D. Circulatory shock. N Eng J Med. 2013;369(18):1726–34.
- Myburgh JA. Fluid resuscitation in acute medicine: What is the current situation? J Intern Med. 2015;277(1):58–68.
- Morgan TJ, Venkatesh B, Hall J. Crystalloid strong ion difference determines metabolic acid-base change during acute normovolaemic haemodilution. Intensive Care Med. 2004;30(7):1432–7.
- Correa TD, Cavalcanti AB, Assuncao MS. Balanced crystalloids for septic shock resuscitation. Rev Bras Ter Intensiva. 2016;28(4):463–71.
- Zhou F, Peng ZY, Bishop JV, et al. Effects of fluid resuscitation with 0.9% saline versus a balanced electrolyte solution on acute kidney injury in a rat model of sepsis. Crit Care Med. 2014;42(4):e270–8.
- Kellum JA, Song M, Li J. Science review: extracellular acidosis and the immune response: clinical and physiologic implications. Crit Care. 2004;8(5):331–6.
- Hadimioglu N, Saadawy I, Saglam T, et al. The effect of different crystalloid solutions on acid-base balance and early kidney function after kidney transplantation. Anesth Analg. 2008;107(1):264–9.
- Yunos NM, Bellomo R, Hegarty C, et al. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA. 2012;308(15):1566–72.
- Reid F, Lobo DN, Williams RN, et al. (Ab)normal saline and physiological Hartmann's solution: a randomized double-blind crossover study. Clin Sci. 2003;104(1):17–24.
- Chowdhury AH, Cox EF, Francis ST, et al. A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and plasma-lyte® 148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers. Ann Surg. 2012;256(1):18–24.
- Shaw AD, Bagshaw SM, Goldstein SL, et al. Major complications, mortality, and resource utilization after open abdominal surgery: 0.9% saline compared to Plasma-Lyte. Ann Surg. 2012;255(5):821–9.
- Young P, Bailey M, Beasley R, et al. Effect of a buffered crystalloid solution vs. saline on acute kidney injury among patients in the intensive care unit. The SPLIT randomized clinical trial. JAMA. 2015;314(16):1701–10.
- Semler MW, Self WH, Wanderer JP, et al. Balanced crystalloids versus saline in critically ill adults. N Eng J Med. 2018;378(9):829–39.
- Self WH, Semler MW, Wanderer JP, et al. Balanced crystalloid versus saline in noncritically ill patients. N Eng J Med. 2018;378(9):819–28.